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Identification and analysis of the genes responsible for inherited neurodegenerative disorders

鉴定和分析导致遗传性神经退行性疾病的基因

基本信息

批准号：
09470041
负责人：
KAKIZUKA Akira
金额：
$ 8.51万
依托单位：
Osaka Bioscience Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470041/
关键词：
neuronal cell death polyglutamine Machada-Joseph disease CAG Repeat PC12 SEK1 stress response Machado-Josephe病 ERDA1 MJD HD

项目摘要

A novel class of inherited human neurodegenerations is now known to be caused by expanded CAG repeats encoding polyglutamines. Polyglutamine-containing protein fragments have been shown to accumulate as aggregates in the nucleus and in the cytoplasm, and to induce cell death when expressed in cultured cells, leading to the proposal that polyglutamine aggregation is an important step in the pathogenesis. Supportingly, nuclear inclusions containing expanded polyglutamines have been identified in neurons from patient brains and in neurons from transgenic mouse models of this class of neural disorders.We analyzed the consequence of polyglutamine expression in PC12 neuronal cells. Activated SEK1 accumulated with nuclear but not cytoplasmic polyglutamine aggregations, which consequently triggers cell death. Cell death induced by polyglutamine expression was inhibited by a dominant-negative SEK1(DN-SEK1), but not by DN-SEKI tagged with a nuclear export signal. Steady state SEKI expression itself was enhanced by two to three fold. Nuclearly aggregated polyglutamines, which were identified in PML bodies, colocalized with not only activated SEKl but also activated c-Jun. We also observed that nuclear inclusion-positive neurons from Huntington disease brains expressed SEK 1.This study provides molecular links between neurodegeneration observed in polyglutamine diseases, cell death signalling kinase cascades, and nuclear subdomains related to cell death. We propose that the nuclear PML bodies containing polyglutamine aggregates activate the SEK1-JNK kinase cascade, resulting in transduction of a death signal.

一类新的遗传性人类神经变性现在已知是由编码多谷氨酰胺的CAG重复扩增引起的。含有聚谷氨酰胺的蛋白片段在细胞核和细胞质中聚集，并在培养细胞中表达时诱导细胞死亡，因此提出聚谷氨酰胺聚集是发病机制的重要步骤。支持这一观点的是，在患者大脑的神经元和这类神经疾病的转基因小鼠模型的神经元中发现了含有扩展的多谷氨酰胺的核内含物。我们分析了聚谷氨酰胺在PC12神经元细胞中的表达。活化的SEK1聚集在细胞核而不是细胞质聚谷氨酰胺聚集，从而引发细胞死亡。显性阴性SEK1（DN-SEK1）可抑制聚谷氨酰胺表达诱导的细胞死亡，而带有核输出信号标记的DN-SEKI则不能。稳态SEKI表达量本身提高了2 ~ 3倍。在PML小体中发现的核聚集的多谷氨酰胺不仅与活化的SEKl共定位，还与活化的c-Jun共定位。我们还观察到来自亨廷顿病大脑的核包涵阳性神经元表达sek1。这项研究提供了在多谷氨酰胺疾病中观察到的神经变性、细胞死亡信号激酶级联反应和与细胞死亡相关的核亚结构域之间的分子联系。我们提出含有聚谷氨酰胺聚集体的核PML小体激活SEK1-JNK激酶级联，导致死亡信号的转导。